9alpha-halo-21-alkane sulfonates of the pregnane series and process therefor



United States Patent 3,000,915 Qa-HALO-Zl-ALKANE SULFONATES OF THE PREG- NANE SERIES AND PROCESS THEREFOR Josef E. Ben and Josef Fried, New Brunswick, N.J., ms to 01in Mathieson Chemical Corporation,

New York, N.Y., a corporation of Virginia No Drawing. Filed June 17, 1955, Ser. No. 516,333 16 Claims. (Cl. 260-39745) This invention relates to the synthesis of valuable steroids; and has for its objects the provision of (I) an advantageous process of preparing steroids of the pregnane (including the pregnene, pregnadiene, and allopregnane) series, unsubstituted in the 21-position, and having a 9a-flu0r0 or chloro (Le. a halogen of atomic weight greater than 18 and less than 36) and an 115- hydroxy (or ll-keto) substituent; (II) certain 2l-alkanesul-fonyloxy and 2l-iodo compounds useful as intermediates in the preparation of these steroids; and (III) certain physiologically active steroids which are new and useful in themselves.

The process of this invention essentially comprises: (a) converting a 21-hydroxy steroid of the pregnane series, having a 9a-fluoro (or chloro) and an llfl-hydroxy (or ll-keto) substituent, into the corresponding 21- alkanesulfonyloxy-derivative thereof; and (b) converting the latter into the corresponding 21-unsubstituted derivative, either directly or through the 2l-iodide derivative.

The novel compounds of this invention comprise: (A) 21-alkanesulfonyloxy-9a-halo-1 1 fl-hydroxy (or 1l-keto)- steroids of the pregnane series; and (B) ZI-iOdO-Qoz-hfllO- 11 fl-hydroxy (or 11-keto)-steroids of the pregnane series; wherein, in each instance, the halogen has an atomic weight greater than 18 and less than 36 (Le. fluoro or chloro).

The preferred compounds preparable by the process of this invention are those which are comprehended by the general formula:

wherein at least one of the positions 1,2; 4,5; and 6,7 is double-bonded, and wherein R is hydrogen, R is hydroxy or together R and R is a keto or ketalized keto group (preferably the free keto group), R" is hydrogen, R'" is fl-hydroxy, or together R" and R is a keto group, X is an a-fillOl'O or a-chloro group, and Z is hydrogen or a-hYdI'OXY.

Representative steroids prcparable by the process of this invention include:

9a-fluoro-1 15,17a-dihydroxyprogesterone;

Qa-Cili oro-l lfi, 17u-dihydroxyprogesterone; 9a-fiuoro-l 1-keto-l7a-hydroxyprogesterone; 9u-chloro-11-keto-l7a hydroxyprogesterone; 9afluoro- 1 1 fl-hydroxyprogesterone;

9a-chloro-l lfl-hydroxyprogesterone;

9a-fluoro-1 l-ketoprogesterone;

9a-chloro-l l-ketoprogesterone; 9u-fluoro-A allopregnene-1 lfl,17a-diOl-3 ,ZO-dione; 9u-chl0ro-A -allopregnene-l 113, 17a-diol-3,20-dione; 9u-fluoro-A -allopregnene-l 7a-ol-3 1 1,20-trione; 9u-chloro-A -allopregnenel7u-ol-3 ,1 1,20-trione; 9a-fluoro-A -allopregnene-l 1 fl-o1-3,20-dione; 9a-chloro-A -a1lopregnene- 1 1p-ol-3,20-dione;

3,000,915 Patented Sept. 19, 1961 2 9a-fluoro-A -allopregnene-3,1 1,20-tn'one; 9a-chloro-A allopregnene-3 ,1 1 ,ZO-trione; 9a-fluoro-A -pregnadiene- 1 1 3, l 7a-diol-3 ,ZO-dione; 9a-chloro-n -pregnadiene- 1 1,8, 17 a-diol-B ,2 O-dione; 9a-iluoro-A -pregnadiene- 17a-o1-3 ,1 1,20-trione; a-chloro-A -*-pregnadiene-17a-ol-3,l 1,20-trione; 9a-fluoro-A -pregnadienel lfl-ol-S ,20-dione; 9u-chloro-A -pregnadiene- 1 1fi-ol-3 ,ZO-dione; 9a-fluoro-A -pregnadiene-ii ,1 1,20-trione; 9a-ch1oro-A -pregnadiene-3,1 1,20-trione; Qa-fluoro-A -pregnadiene- 1 1,5, 1 7ot-di013,20-dl0116 9a-chloro-A -pregnadiene1 115, 17a-diol-3,20-dione; 9e-fluoro-n -pregnadienel7u-0l-3,l 1 ,20-trione; 9u-chloro-A -pregnadiene- 17a-0l-3,1 1,20-trione; 9a-fluoro-A "-pregnadiene- 1 1 fl-ol-3,20-dione; 9a-chloro-A -pregnadiene-1 lB-ol-Z ,ZO-dione; 9a-fluoro-A -pregnadiene-3,11,20-trione; and 9a-chloro-A -pregnadiene-B,1 1,20-trione.

To prepare these 9a-halo compounds, a steroid of the general formula CHIOH wherein at least one of the positions 1,2; 4,5; and 6,7 is double bonded and R, R, R", R, X, and Z are as above-defined, is reacted with an alkancsulfonyl halide. Representative steroids suitable as initial reactants in the process of this invention are disclosed in US. applications, Serial No. 489,769, filed February 21 ,1955, and Serial No. 417,489, filed March 10, 1954, now U.S. Patent No. 2,852,511, by Josef Fried, and include:

9a-fluoro-hydrocortisone;

9a-chlorohydrocortisone;

9a-fluorocortisone;

9a-chlorocortisone;

9a-fluorocorticosterone;

Qa-ChIOIOCOItiCOStCl'OIlB;

9a-fluoro-1 l-dehydrocorticosterone;

9oz-Chl0I'O-1 l-dehydrocorticosterone; 9a-fluoro-A -allopregnene-1 l B, 1 701,21 -triol-3 ,ZO-dione; 9a-chloro-A -allopregnene-l 1,6, 17:1,2 l-triol-3 ,ZO-dione; 9a-fluoro-A -allopregnene-l7a,21-diol-3 ,1 1,20-trione; 9ach1oro-A -a1lopregnene-l7a,2 1diol-3 ,1 1,20-trione; 9a-fluoro-A -allopregnene-1 1,6,21-diol-3 ,ZO-dione; 9a-chioro-A -aliopregnene-1 118,21-diol-3 ,ZO-dione; 9a-fiuoro-A -a.llopregnene-2 1-ol-3 ,1 1 ,20-trione; 9a-chloro-A -allopregnene-2 1-ol-3 ,1 1 ,20-trione; 9a-fluoro-A -pregnadiene-1 1B, 1 701,2 1-trio1-3 ,20-dione; 9a-chloro-A -pregnadiene-11B,17u,21-triol-3,20-dione; 9-fluoro-A -pregnadiene-17a,21-diol-3 ,1 1,20-trione; 9a-chloro-A -pregnadiene-17a,21-di013,l 1,20-trione; 9a-fluoro-A -p regn adiene-l 13,21-di01-3 ,ZO-dione; 9a-chloro-A -pregnadienel l 5,2 ldiol-3 ,20-dione; 9a-fiuoro-A -pregnadiene-Z1-ol-3,11,20-trione; 9a-chloro-A'- -pregnadiene-2l-ol-3,1 1 ,ZO-trione; 9a-fluoro-A -pregnadiene-1 1;8,17a,21-triol-3 ,ZO-dione; Qa-chIOrO-A regnadiene-I 1fi,17a,21-triOl-3 ,ZO-dione; 9a-fluoro-n pregnadiene-l7a,21-diol-3 ,1 1,20-trione; 9a-chloro-A -pregnadienel7rx,21diOi-3 ,1 1,20-trione; 9a-fluoro-A -pregnadiene-1 l fl,21-diol-3 ,ZO-dione; 9m-chloro-A*'-pregnadiene- 1 lfi,21-diol-3,20-dione; 9a-fiuoro-n -pregnadiene-21-ol-3,l1,20-trione; and 9a-chloro-M- -pregnadiene-21-o1-3,1 1,20-tn'one.

These steroids are reacted with an alkanesulfonyl halide (sulfonyl chlorides are preferred, but other halides such as bromides and iodides may be used). Although any alkanesulfonyl chloride may be used, the alkane group is preferably a lower alkane, methanesulfonyl chloride (mesyl chloride) being particularly preferred. The re action is carried out by intermixing the steroid and sulfonyl halide under substantially anhydrous conditions and preferably in the cold (e.g. at a temperature less than about C.), in the presence of pyridine or other organic base.

The reaction results in the production of new intermediate steroids containing in the 2l-positlon an alkanesulfonyloxy radical, which corresponds to the alkanesulfonyl halide used in the reaction. The preferred intermediate 2l-alkanesulfonyloxy compounds of this invention are those of the following general formula CHaOSOaR wherein at least one of the positions 1,2; 4,5; and 6,7 is double-bonded, and wherein R"" is alkyl (preferably lower alltyl), and R, R', R", R'", X and Z are as hereinbefore defined.

These 21-alkanesulfonyloxy intermediates are then reacted with a metal iodide (such as an alkali metal iodide, and particularly sodium iodide) in an organic solvent. The reaction is preferably, but not necessarily, conducted at an elevated temperature {c.g. at reflux). The nature of the product will depend on the organic solvent selected. If an acidic solvent, such as a lower alkanoic acid (particularly glacial acetic acid) is chosen, the 2l-unsubstituted final products of this invention are obtained directly. If, however, a neutral solvent such as an alcohol or a ketone (particularly acetone) is selected, then the 2l-iodated intermediates of this invention are produced. The preferred 21-iodo compounds of this invention are those of the general formula CHzI R l s 7 wherein at least one of the positions 1,2; 4,5; and 6,7 is double-bonded, and wherein R, R, R", R', X and Z are as hereinbefore defined.

These 21-iodo intermediates can then be converted to their ZI-unsubstituted derivatives, either in situ or in a second step by reacting (preferably by heating) the former with an alkali metal iodide in an acidic solvent or with a metal bisulfite (such as an alkali metal bisulfite, particularly sodium bisulfite) in an inert solvent, such as an aqueous organic solvent (e.g. water-dioxane), or with an electropositive reducing metal (such as zinc dust) in an acidic solvent to prepare the final products of this invention.

The steroids of the pregnane (including the pregnene, pregnadiene, and allopregnene) series of this invention, which are unsubstituted in the 2l-position, and have a 9a-flu0ro (or chloro) group and an llfi-hydroxy (or 11- keto) group are physiologically active compounds, which glucocorticoid as well as mineralocordcoid activity. Thus, the new steroids of this invention can be administered instead of, and in the same manner as, cortisone of hydrocortisone in the treatment of rheumatoid arthritis and dermatomyositis, or in the same manner as desoxycoiticosterone in the treatment of Addisons disease or adrenal insufiiciencies. In the latter instance, it is especially advantageous since the compounds can be administered perorally, whereas desoxycorticosterone has to be given by injection. The dosage for such administration is, of course, dependent on the relative activity of the compound.

The following examples are illustrative of the invention (all temperatures being in centigrade). The first four examples are directed to processes for preparing the 2ialkanesulfonyloxy intermediates of this invention:

EXAMPLE 1 9a-fluorohydrocortisone 21 -mesylare To a solution of 4 g. of 9a-fluorohydrocortisone in 50 ml. of anhydrous pyridine is added at 0' with stirring 21.1 ml. of methanesulfonyl chloride. After 3 hours at 0", ml. of ice water is added which induces rapid crystallization of the mesylate. After short standing at 0 the crystals are filtered ofl and washed first with a mixture of equal volumes of acetone and water and finally with ice-water, keeping the acetone-water washes separate from the original pyridine-containing mother liquor. The dried crystals weigh about 4 g. equal to approximately 83% of theory and melt at about 228 (dec.). Concentration of the acetone-water washes yields an ad ditional mg, M.P. about 220 (dec.). Recrystallization from ethyl acetate furnishes the pure 9u-flnorohydrocortisone mesylate possessing the following properties, M.P. about 226-227 (dec.); [a] +l29 (c., 0.30 in dioxane);

kg; 238 m (e=20,800); A221? 2.82;;

2.94 (OH), 5.77n (20-keto), 6.04 618 (A -3-ketone).

Analysis.-Calcd. for C2gH3107FS (458.53): C, 57.62; H, 6.82; S, 6.99. Found: C, 57.92; H, 6.80; S, 7.39.

In a similar manner by substituting an equivalent amount of 9a-chlorohydrocortisone, 9a-fluorocorticosterone, 9a-chlorocorticosterone, 9u-fl1101'0 ll dehydrocorticosterone, or 9a-ch1oro-1 l-dehydrocorticosterone, for the 9a-fluorohydrocortisone in example, 9u-chlorohydrocortisone ZI-mesylate, 9n-fluorocorticosterone 21-mesylate, 9a-chlorocorticosterone 2l-mesy1ate, 9a.-fluoro-11-dehydrocorticostenone 2l-mesylate, and 9a-chloro-11-dehydrocorticosterone ZI-mesylate are prepared, respectively.

Although 9a-fluctrocortisone 2l-mesylate and 9a-chlorocortisone 21-mesyl-ate may be prepared analogously, by substituting either 9a-fluorocortisone or 9a-chlorooortisone for the 9a-fluorohydrocortisone in the procedure of Example I, an alternative method for forming these ll-keto derivatives is illustrated by the following example, wherein 9a-fluorohydrocortisone ZI-methylate is oxidized with an oxidizing agent, such as a hcxavalent chromium compound (e.g. chromic acid) in an organic acid solvent, such as glacial acetic acid, to 9a-fluorocortisone 2l-mesylate.

EXAMPLE 2 To a solution of 460 mg. of 9a-fluorohydrocortisone 2l-mesylate in 20 ml. of glacial acetic acid is added over a period of five minutes a solution of 100 mg. of chromic acid in 5 ml. of acetic acid. After an additional 10 minutes at room temperature V2 ml. of alcohol is added to destroy excess chromium trioxide and the solution concentrated in vacuo to small volume. The residual syrup is distributed between chloroform and water, and the chloroform solution washed with water, dilute sodium bicarbonate solution and again with water. After A12 234 my (e=l8,500); ml? 2.92;. (OH) 5.79 (20-kel0), 6.02 4, 6.19 (A -3-ket0ne).

Analysi.r.alcd. for C H O FS (456.51): C, 57.88; H, 6.40; S, 7.02. Found: C, 58.04; H, 6.47; S, 7.08.

EXAMPLE 3 9a fluoro A pregnadiene-II5,17a,21-triol-3,20-dione 21 -mesylate [1,2-dehydro-9a-flu0rohydrocortisone 21- merylate] To a solution of 50 mg. of LZ-dehydrO-Qa-fluomhydrooortisone acetate in 3 ml. of methanol is added under nitrogen 0.6 ml. of a aqueous potassium carbonate solution, which has been boiled for 1 minute and cooled under nitrogen. Aliter & hour at room temperature 0.1 m]. of glacial acetic acid and 2 ml. of water are added and the methanol taken off in vacuo. The crystalline 1,2- dehydro-9a-fluorohydrocortisone is centrifuged oil and recrystallized from 95% alcohol. The pure substance has the following properties, M.P. about 274-275 (doc), [11.1 +94 (c., 0.29 in 95% alcohol).

To a solution of 34 mg. of 1,2-dehydro 9s-fluorohydrocortisone in 1 ml. of anhydrous pyridine is added at 0 a solution of 0.05 ml. of methanesulfonyl chloride in 0.5 ml. of chloroform. After 2% hours at 0',*ice and water are added and the mixture extracted with ethyl acetate. The ethyl acetate extract is washed with dilute sulfuric acid, water, dilute sodium bicarbonate solution and again with water and dried over sodium sulfate. Evaporation of the solvent leaves a crystalline residue which represents essentially pure l,2-dehydro-9m-fiuoro hydrocortisone 21-mesylate, M.P. about 218-219" (dec.).

In a similar manner, by substituting 9a-chloro-A pregnadiene-l lB,17a,2l-triol 3,20 dione ZI-acetate, 9a fluoro-A -pregnadiene-11,8,21-diol-3,20-dione ZI-acetate, 0r 9a-chloro-A -pregnadiene-llp,2l-diol-3,20-dione 2,1- acetate for the 9a-fluoro-A -pregnadiene11p,17u,2ltriol-3,20-dione 2l-acetate in Example 3, the corresponding 21-mesylates are prepared. The 9a-fluoro-A -pregnadiene-l1,6,17a,2l triol-3,20-dioue 21-mesylate of Example 3, or the corresponding Qa-ChIOrO and/or 17a-desoxy derivatives can be oxidized to the corresponding ll-keto derivatives by the method of Example 2, thereby forming 9a-fiuoro-A -pregnadiene-17a,2l-diol-3, 1 1,20-trion 21 mesylate and the analogous 9a-Ohl010 and/or 17e-desoxy derivatives.

EXAMPLE 4 9a-flu0r0-A--pregnadiene-11fl,17a,2l-tri0l-3,20-dione 2i mesylate [6,7 dehydro 9a fluorohydrocortisone 2]- mesylate] To a solution of 250 mg. of 6,7-dehydro-9a-lluorohydrocortisone acetate in 7.5 ml. of methanol is added under nitrogen a solution of 1.2 ml. of a 10% aqueous potassium carbonate solution, which has been boiled-for Analysis.-Calcd. for (41H3105F (378.43): C, 66.65; H, 7.19. Found: C, 66.30; H, 7.00.

To a solution of 175 mg. of 6,7-dehydro-9u-fluorohydrocortisone in 4 ml. of dry pyridine is added at 0 :1 solution of 0.1 ml. of methanesulfonyl chloride in 1 ml. of chloroform. After 2% hours at 0 ice water is added and the mixture extracted with chloroform. Extraction of the chloroform solution with dilute sulfuric acid, water, sodium bicarbonate solution and water followed by evaporation of the chloroform in vacuo furnishes a residue consisting of essentially pure 6,7-dehydno-9afluorohydrocorusone zl-mesylate. Recrystallization from 95% ethanol yields the pure mesylate having the following properties: M.P. about 237-238 (dec.) [121 +94 (c., 0.21 in 95% alcohol);

A3,, 281 my (e=27,500) Amt 285p 2.98s (OH), 5.76 1 (ZO-keto), 6.05 6.10 1, 6.18, 6.30; (A -3-ketone).

Analysis.Calcd. for CggHggO'qFS (45 6.51): C, 57.78; H, 6.40; S, 7.02. Found: C, 58.19; H, 6.05; S, 7.54.

In a similar manner, by substituting the 2lacetoxy de rivatives of 9u-ChlOr0-A -p1'egl1adi6He-l1B,17a-di01-3,20- dione, 9u-fluoro-A -pregnadiene-1 I13 ol 3,20-dione, or 9a-chloro-A -pregnadiene-llfi-ol-3,20-dione for the 90:- fluoro-d -pregnadiene-l 1fl,17u,2l triol 3,20-dione 21- acetate in Example 4, the corresponding 2l-mesylates are prepared. These llfi-hydmxy steroids can then be oxidized by the method of Example 2 to the corresponding ll-keto derivatives, yielding 9e-fluoro-A -p-regnadiene-l7m,21-dioI-3,l1,20-trione 2l-mesylate or the analogous 9a-chloro and/or l7a-desoxy derivatives.

Furthermore, the procedures of Examples 3 and 4 are also operative in the conversion of 9u-fluoro (or chloro)- A -a.llopregnene-llfl,17u,2l triol 3,20-dione ZI-acetate and 9a-fluoro (or chloro)-A allopregnene-11fi,2l-diol- 3,20-dione 2l-acetate to the corresponding 2l-mesylate derivative and the subsequent oxidation of the resulting 21-mesylate to the corresponding ll-keto product.

Although the sulfonyl halide employed in each of the processes of Examples 1 through 4 is the methanesulfonyl chloride, other alkanesulfonyl halides, such as the lower alkanesulfonyl chlorides (cg. ethane-sulfonyl chloride) may be used to yield the corresponding 2l-alkanesu-lfonyloxy (erg. ethanesulfonyloxy) derivative.

The following four examples are directed to processes for preparing the 21-iodo intermediates of this invention from the corresponding 2l-alkanesulfonyloxy intermediates EXAMPLE 5 A solution of 500 mg. of 9a-fiuorohydrocortisone 21- mesylate and 1.5 g. of sodium iodide in 15 ml. of acetone sulfate. Evaporation of thesolvent leaves a crystalline residue consisting ementinlly of 6,7-dehydro-9a-fluoro-:.

hydrocortisone. After recrystallization from 95% ethanol the substance has the following properties: MJ about 257-259 (dec.); [(11, +10l (c., 0.45 in 95% ethanol);

A;',:-, 281 m (e=25,600) A52: 2.95 (OH) 5.85 1 (ZO-keto), 6.10;, 6.19;, 6.31 1 (A -B-Itetone).

is refluxed for 10 minutes. During the reaction period sodium mesylate precipitates throughout the solution. Hot water is then added until the sodium mesylate is dissolved and the solution is allowed to cool in the refrigeraafter one recrystallization from acetone-hexane have the following properties, M. P. ca. 300 (dec.); Ed -{429 (c., 0.45 in dioxane);

M3; 238 m (e=18,700); ARR? 2.87;;

3.04 (OH), 5.88 (20-ket0), 6.06 1 (A -3-ketone).

Analysis-Calm. for C H OJ- I (419.35): C, 51.43;

H, 5.76; I, 25.88. Found: C, 51.08; H, 5.75; I, 25.02

In a similar manner by substituting an equivalent .amount of the 21-mesylate of 9a-chlorohydrocortisone,

The 2l-iodide crystallizes in long needles which 7 EXAMPLE 6 9a. -fluro -21- iodo -A pregnene 7-a-al- 3,11,20- trione 9a-fluoro-2I -iodo-1 I -ket0-17a-hydroxyprogesterone] A solution of 340 mg. of 9a-fiuorocortisone ZI-mesylate and 1.5 g. of sodium iodide in 15 ml. of acetone is refluxed for minutes. Hot water is then added to dissolve the precipitated sodium mesylate and the resulting solution is allowed to crystallize at 0. After recrystallization of the material from acetone-hexane the pure iodo-compound is obtained having the following properties, M.P. ca. 300 (dec.), browning at 150; [uJ -I- 128 (c., 0.35 in chloroform);

Nil 234 a 553?" 5.82; (20-keto), 6.05 (A -3-ketone).

Analysis-Calm. for C l-1 0 1 (488.34): C, 51.65; H, 5.34; I, 25.99. Found: C, 52.54; H, 5.41; I, 26.15.

Similarly 9a-chloro-21 -iodo-A-pregnene- 1 7a-Ol-3,1 1,20- trione, 9a-fluoro-21-iodo-A -pregnene-3,11,20-trione, and 9o.-chloro-2l-iodo d -pregnene,11,20-trione can be obtained from the 2l-mesylates of 9a-chlorocortisone, 9afluoro-ll-dehydrocorticosteronc, and 9a-chloro-ll-dehydrocortieosterone, respectively.

These ll-keto derivatives can also be prepared from the corresponding 21-iodo-llp-hydroxy derivatives by oxidation with chromic acid in glacial acetic acid.

EXAMPLE 7 9m-fluoro-2I -iodo-A -pregnadiene-1 13,1 7 a-diol- 3 ,ZO-diane A solution of 36 mg. of l,2-dehydro-9efluorohydrocortisone 2l-mesylate in 1.5 ml. of acetone and 120 mg. of sodium iodide is refluxed for 10 min. Water is added and the acetone removed in vacuo. The aqueous suspension of the 21-iodo derivative is taken up in ethyl acetate and extracted several times with water. The ethyl acetate solution is dried over sodium sulfate and evaporated to dryness. The residue constitutes essentially pure 9afluoro-2l-iodo-n -pregnadiene-llfl,17a-diol-3,20 dione, M.P. about 180-195 (dec.).

In a similar manner, by substituting the 2l-mesyloxy derivatives of 9a'chloro-A -pregnadiene 1la,17or diol- 3.20-dione, 9er-fluoro-A -pregnadiene-l-01-320 dione, 9e-chloro-A -pregnadiene-l 15-01-3 ,20-dione, 9a fluoroa -pregnadiene-17a-ol-3,11,20 trione, 9n chloro A pregnadiene-17a-ol-3J1,20-trione, 9a fluoro A pregnadiene-3,ll,20-trione, or 9a-chloro A pregnadiene- 3,11,20-trione for the 21-mesylate of 9a-fluoro-A -pregnadiene-l1,9,l7a,2l-triol-3,20-dione in Example 7, the corresponding 2l-iodo derivatives are formed.

EXAMPLE 8 A solution of 190 mg. of 6,7-dehydro-9a-fluoro-hydrocortisone 2l-mesylate and 723 mg. of sodium iodide in 7.2 ml. of acetone is refluxed for 10 minutes. The reaction mixture is diluted with water until all the sodium mesylate has dissolved. The solution is allowed to cool slowly. After concentration in vacuo the crystals are filtered and recrystallized from ethanol. Pure 9a-fluoro- Zl-iodo-A -pregnadiene-IlB,17e-diol-3,20-dione has the following properties: M.P. about 225 (dec.); [ah -+110 (c., 0.33 in absolute alcohol);

5.85 (-keto), 6.08;. 6.18;, 6.311; (A -3-ketone).

Analysis-Calm. for C l-1 0 1 1 (488.34): C, 51.65; H, 5.37; I, 2599. Found: C, 51.93; H, 5.68; I, 26.58.

In a similar manner, by substituting the 21-mesyloxy derivatives of 9a chloro-A -pregnadiene-l18,17a-diol- 3,20-dione, 9a-fluoro-A -pregnadiene-1lfi-ol-3,20-dione, 9a-ChlOrQ-A- pregnadiene-1 1fl-ol-3,20-dione, 9a. fluoro- 8 M -pregnadiene-U n-ol-3,11,20-trione, 9a chloro A pregnadiene-l7a-ol-3,l1,20-trione, 9a-fluoro-A -pregnadiene-3,1 1,20-trione, and 9a-chloroA -pregnadiene-3,1 l- ZO-trione for the 9m-fluoro-A -pregnadiene-11p,l7a,21- triol-3,20-dione 2l-mesylate of Example 8, the corresponding 21-iodo derivatives are produced.

Furthermore, the procedures of Examples 5 through 8 are also operative in the conversion of 9m-fluoro (or chloro)-A -allopregnene-11fl,l7a,21-triol-3,20 dione 21- mcsylate, 9a-fluoro (or ehloro)-A -allopregnene-17a,21- diol-3,ll,20-trione 2l-mesylate, 9a-fluoro (or chloro)- A' -ailopregnene-l1B,21-dio1-3,20-dione 2l-mesylate, and 9a-fluoro (or chloro)-A -allopregnene 21 ol 3,11,20- trione 2l-mesylate to their respective 21-iodides.

The following examples are directed to processes for preparing the 2l-unsubstituted final products of this invention. As shown by these examples, the ZI-unsubstituted products can be prepared either directly from the ZI-mesylates of Examples 1 through 4 or from the 21-iodides of Examples 5 through 8.

EXAMPLE 9 9a-flu0ro-I 1 p8,] 7a-dihydroxy progesterone from 9a-fluorohydrocortisone ZI-mesylate A solution of 180 mg. of 9a-fluorohydrocortisone 2lmcsylate and 600 mg. of sodium iodide in 20 ml. of glacial acetic acid is refluxed for one hour. The mixture is concentrated to small volume and diluted with chloroform. The chloroform solution is washed with sodium sulfite solution, water, sodium bicarbonate solution and again with water. After drying over sodium sulfate the chloroform is evaporated in vacuo and the resulting crystalline residue consisting of 9a-fluoro-l1fl,17-dihydroxyprogesteroue is recrystallized from 95% ethanol. The analytically pure substance melts at about 274-276 and is identical in all respects with an authentic sample of 9u-fluoro-llfl,17a-dihydroxyprogesterone.

Analysis.-Calcd. for C H O F (364.44): C, 69.20; H, 8.02. Found: C, 69.22; H, 7.93.

EXAMPLE l0 a-flMOfO-I 1 3,1 7-dihydroxyprogesrerone from 9a-fluoro- 21 -iodo-A*-pregnene-I 13,1 7a-di0l -3 ,20-di one To a solution of 3.1 1 g. of 9a-fluoro-2l-iodo-M-pregnene-l 1fi,17u-diol-3,20-dione in 31 ml. of dioxane is added 31 ml. of a 5% solution of sodium bisulfite in water. The resulting mixture is heated on the steam bath for 30 min. during which period the desired 9u-fluoro-l1p,17udihydmxyprogesterone begins to crystallize. After cooling in the refrigerator the crystals amounting to about 2.1 g. or approximately of theory are filtered oil and washed thoroughly with water. The product obtained in this manner melts at about 275-277 and represents pure 9a-fluoro-11fi,l7u-dihydroxyprogesterone. An additional amount of material is recovered from the dioxane-water mother liquor.

EXAMPLE 11 A solution of 150 mg. of 9a-fluoro-2l-iodo-A -pregnene-l7e-ol-3,1l,20-trione and 500 mg. of sodium iodide in 15 ml. of glacial acetic acid is refluxed for one hour. The mixture is concentrated to small volume in vacuo, taken up in chloroform and extracted with sodium bisulfite solution, water, sodium bicarbonate solution and again with water. After drying over sodium sulfate the solvent is removed in vacuo and the resulting crystalline residue consisting of 9a-fluoro-l7a-hydroxy-ll-ketoprogesterone recrystallized from ethanol. The resulting product is identical in all respects with an authentic sample.

9a-fluoro-17c-hydroxy-1l-ketoprogesterone can also be obtained by reduction of the ZI-iodo compound with sodium bisulfite in dioxane-water as described in Example 10 or by reduction of the 2l-mesylate with sodium iodide in acetic acid as described in Example 9.

In the same manner, by substituting either the 21- mesylate of 9a-chlorohydrocortisone, 9ufluorocorticosterone, 9a-chlorocorticosterone, 9a-fluoro l1 dehydrocorticosterone, 9echloro ll dehydrocorticosterone, or 9e-chlorocortisone in the procedure of Example 9, or the 2l-iodide of 9u-chloro-A -pregnenel1p,l7a-dio1-3,20- dione, 9a-fluoro-A -pregnene-llfl-ol-3,20-dione, 9e-chloro- M-pregnene-llfl-ol-3,20-dione, 9wfluoro-A -pregnene-3, 11,20-trione, 9e-chloro-n -pregnene-3J1,204rione, 9achloro-A -pregnenel7u-ol-3,11,20-trione in the procedure of Example 10 or 11, 9-chloro-11p,17a-dihydroxyprogesterone, 9e-fluoro-1 lfl-hydroxyprogesterone, 9a-chlorol lp-hydroxyprogesterone, 9a-fil101'O-1 l-keto-progesterone, 9a-chloro-ll-ketoprogesterone, and -;9e-chloro-l1-keto- 17u-hydroxyprogesterone are prepared, respectively.

A solution, of 37.8 mg. of 9a-fluoro-21-iodo-A --pregnadiene-llp,l7a-diol-3,20-dione in 1 ml. of purified dioxane and 1 m1. of 5% aqueous sodium bisulfite is refluxed on the steam bath for to hour, the resulting crystals are centrifuged 0E and washed with several portions of water. Recrystallization from 95% ethanol furnishes pure 9m-fluor0-A pregnadiene-1lp,l7a-diol-3, ZO-dione possessing the following properties, M.P. about 313-315 (dec.); lab" +47 (c., 0.20 in pyridine);

3,, 238 m $15,500); iii? 5.85 4. (ZO-keto), 6.03;, 6.201;, 6.25 1. (A -3-ketone).

AnaIysis.-Calcd. for C H O F (362.42): C, 69.59; H, 7.50. Found: C, 69.47; H, 7.66.

To a solution of 140 mg. of 9a-fluoro 21-iodo-A*-- pregnadiene-llfl,l7u-diol-3,20-dione in 1.4 m1. of pure dioxane is added 1.4 ml. of 5% aqueous sodium bisulfite solution. The mixture is heated on the steam bath for /2hour and during this process crystals appear throughout the solution. After the addition of water, the mixture is cooled and the crystals of 9a-fluoro-A -pregnadiene- 1lfi,l7u-diol-3,20-dione are filtered oil and washed with water. Recrystallization of the crude crystals (about 92 mg.) from 95% ethanol furnishes the pure compound having the following properties: M.P. about 1294-296 (dec.); [al +112 (c., 0.33 in dioxane);

M3,, 281 mp (e=26,000) 12:23 2.99;; (OH) 5.87 (ZO-keto), 610p, 6.18;, 6.30 4 (A -S-ketOne).

1 Analytic-Called. for C l-1 0.1 (362.43) C, 69.59; H, 7.51. Found: C, 69.66; H, 7.48.

In the same manner as Example 13 or in an analogous manner to Example 9, the 2l-iodo and Zl-methanesultonyloxy derivatives of can be converted to their respective ZI-unsubstituted derivatives.

Furthermore, the procedures of Examples 9 through 13 are also operative in the conversion of the 2l-methanesulfonyloxy or 2l-iodo derivatives of 9a-fluoro (or chloroJ-A -alloprcgnene-l1fi,17st-diol-3,20-

dione,

Qa-fluOro (or chloro)-A -allopregnene-1lB-ol-3,20-dione,

9a-fiuoro (or chloro)-A -allopregnene-17a-ol-3,11,20-trione, and

9a-fluoro (or chloro)-A -allopregnene-3,l1,20-trione to their corresponding zl-unsubstituted derivatives.

The invention may be otherwise embodied within the scope of the appended claims.

We claim:

1. 9a-halo-hydrocortisone 21-(lower alkane)sulfonate, wherein the halogen has an atomic weight greater than 18 endless than 36.

2. 9a halo cortisone 2l-(lower alkane)sulfonate, wherein the halogen has an atomic weight greater than 18 and less than 3.6.

3. 9e-halo A pregnadiene-llA,l1a,2l-tri0l-3,20- dione 2l-(lower alkane) sulfonate, wherein the halogen has an atomic weight greater than 18 and less than 36.

4. 9e-halo 21 iodo-M-pregnene-llp,17a-diol-3,20- dione, wherein the halogen has an atomic weight greater than 18 and less than 36.

5. 9a halo-Zl-iodo-M-pregnene-17e-ol-3,l1,20-trione, wherein the halogen has an atomic weight geater than 18 and less than 36.

6. 9c: halo-21-iodo-A*-pregnadiene-l 1p,17a-diol-3 ,20- dione, wherein the halogen has an atomic weight greater than 18 and less than 36.

7. The process which comprises reacting a Zl-alkanesulfonyloxy steroid of the pregnane series, having a 9dsubstituent selected from the class consisting of fluoro and chloro, and an ll-substituent selected from the class consisting of fl-hydroxy and keto, with a metal iodide in an acidic organic solvent, and recovering the ZI-unsubstituted steroid thus produced.

8. The process which comprises reacting a steroid of the pregnane series, having a 9u-substituent selected from the class consisting of fluoro and chloro, an ll-substituent selected from the class consisting of fi-hydroxy and keto, and a Zl-substituent selected from the class consisting of alkanesulfonyloxy and iodo, with a reactant selected from the group consisting of a metal bisulfite, a metal iodide in an acidic solvent and an electropositive metal, and recovering the ZI-unsubstituted steroid thus produced.

9. A compound selected from the group consisting of steroids of the general formulae wherein R" is hydrogen, R' R" and R ing of Ct-fiUOI'O and a-ChlOI'O, Z is selected from the group consisting of hydrogen and a-hydroxy, and R'' is lower is fl-hydroxy and together is keto, X is selected from the group consistalkyl. 16 10. A compound selected from the group consisting of steroids of the general formulae (ZH I 011,1 C=O (i=0 20 RH RI! ---.z ,W ,mg /\/g\/ f s) O- O OHII I so

and 0: 0a:

wherein R" is hydrogen, R'" is fl-hydroxy and together R" and R' is keto, X is selected from the group consisting of a-fiUOl'O and a-chloro, and Z is selected from the group consisting of hydrogen and fi-hydroxy.

11. 9a-fluorohydrocortisone 21-mesylate.

12. 9u-fluorocortisone 21-rnesylate.

13. 9a-fluoro A pregnadieue-l1fl,17a,21-triol-3,20- dione 21-mesylate.

14, 9a-fluono 21 iodo-M-pregnene-l1fi,17a-dioI-3,20- dione.

15. 9oz fiuoro-Zl-i0do-A*-pregnene-17a-ol-3,11,20-trione.

16. 9a-fluoro 21 iodo-A --pregnadiene-1lfl,l7u-diol- 3,20-dione.

References Cited in the file of this patent UNITED STATES PATENTS 2,183,589 Reichstein Dec. 19, 1939 2,703,799 Bergstrom Mar. 8, 1955 2,707,190 Farrar Apr. 26, 1955 2,713,587 Bergstrom July 19, 1955 2,736,681 Tishler Feb. 28, 1956 2,736,734 Sarett Feb. 28, 1956 2,763,671 Fried et a1 Sept. 18, 1956 2,837,464 Nobile June 3, 1958 2,852,511 Fried Sept. 16, 1958 2,875,200 Hogg et a1 Feb. 24, 1959 2,912,446 Sarett Nov. 10, 1959 OTHER REFERENCES Fried et al., Jour. Am. Chem. 800., 75, 2273 (1953). Fried et al., Iour. Am. Chem. 800., 76, 1455-1456 (1954). 

1. 9$-HALO-HYDROCORTISONE 21-(LOWER ALKANE)SULFONATE, WHEREIN THE HALOGEN HAS AN ATOMIC WEIGHT GREATER THAN 18 AND LESS THAN
 36. 